This renewal application proposes three projects and three cores to extend studies of phenotypes associated with autism. The Immune Component will address four specific aims: 1) investigate the interaction between serotonin and immune dysregulation; 2) characterize the specificity and autoreactivity of T cells and antibodies in subjects with autism; The Genetics Component will collect DNA and clinical information on affected cases and relatives (including intermediate phenotypes, broader autism phenotype, head circumference, serotonin levels, and stored serum for immune phenotypes identified by the Immune Component). Assessments will be done on five extended Utah kindreds already identified through the Utah Population Data Base, and on two new extended pedigrees to be identified through a new UPDB search of 800 new autism cases identified through surveys and the State Health Department and University of Utah Clinics. A 5 cM genome scan will be done using the Marshfield Mammalian Genotyping Service. Pedigrees will be analyzed using the clinical phenotype and intermediate phenotypes to map susceptibility loci. Five candidate genes under linkage peaks and/or identified by the Immune Component will be genotyped using SNPs. DNA, whole blood (for future serotonin), and serum (for future immune phenotyping) will be stored on the 800 new autism cases and their parents for future family-based association studies. The Neuroimaging Component will study persons with autism, employing structural and functional imaging studies to address the following specific aims: 1) describe longitudinal changes in structural brain volumes and their relationships to changes in clinical phenotypes; 2) describe relationships among brain structure, white matter structure and integrity, brain activation, and brain chemistry; 3) study associations between abnormalities of the brain and immune function (as assessed by the Immune Component). Subjects will overlap with those studied by the Immune Component. COMPONENT PROJECTSPROJECT I Immunology (Robert Fujinami, Ph.D., pp. 96-130) DESCRIPTION [provided by applicant]: The Immunology Project proposes to investigate the role of serotonin in inducing dysregulation of the immune response. The investigator will examine the specificity and autoreactivity of T cells and antibodies present in children with autism. He will determine whether immune effector cells and antibodies induce or mimic CNS features often observed in autistic subjects such as hippocampal and mammillary body changes. Finally, he proposes to perform microarray analyses on RNA isolated from peripheral blood mononucler cells of autistic children versus control subjects.